Mucosal remodeling due to vocal fold irritation, infection or injury causes poor voice quality which can result in significant psychosocial and financial costs to the individual. The biological mechanisms underlying vocal fold mucosa remodeling are not known. However, compromised epithelial integrity is implicated in acute and chronic mucosal remodeling in other airway tissue;when epithelium is damaged, its role as a physical and biochemical barrier protecting underlying tissue from insults from the external environment is lost. Rapid and complete restoration of a fully developed epithelium following injury is therefore critical to promote mucosal defense and healing. Our long-term goal is to identify the role of vocal fold epithelial cells in modulating mucosal remodeling in response to injury in order to improve prevention and management of voice disorders. The overall objective of this proposal is to develop a detailed timeline of molecular, cellular and functional changes in epithelium during the acute and chronic phases of wound repair. Concurrent examination of cellular and extracellular changes in lamina propria will permit a holistic analysis of vocal fold mucosal wound healing. We will implement a prospective, double-blind, randomized, controlled experimental study in an animal model to examine cellular and molecular changes in vocal fold epithelium following acute injury. Immuno-histochemistry using transmission electron microscopy and light microscopy and permeability assays will be performed to assess restoration of intercellular and cell-substrate junctions, determine epithelial barrier integrity, and examine the distribution of epidermal growth factor receptors (EGFR) and two growth factors that regulate EGFR activation (EGF and TGF2) in epithelium at critical time points following injury. Chronic aberrant or incomplete epithelial regeneration of cell junctions, persistent 'leakiness'or atypical distribution of EGFR will indicate that vocal folds are at risk for ongoing inflammation, perpetuation of mucosal remodeling, and development or recurrence of vocal fold pathologies post injury. Results of the proposed study will have a significant impact on the field of laryngology, because knowledge of cellular and molecular changes in epithelium during wound healing, when integrated with our understanding of remodeling in the lamina propria following injury, will allow development of a holistic model of mucosal repair;provide a basis for examining epithelial-mesenchyme interactions in wound healing;and add to the knowledge base needed to develop novel cytoprotective interventions to hasten and optimize mucosal repair following surgery as well as following other mechanical, chemical, and biological insults. PUBLIC HEALTH RELEVANCE: Knowledge of the changes in epithelial structure and function accompanying epithelial regeneration following injury, when evaluated in the context of concurrent cellular and extracellular changes in lamina propria, will provide a basis for examining epithelial-mesenchyme interactions in wound healing and for the development of cytoprotective interventions and regenerative treatments to minimize scarring and maximize patient outcomes following surgery. It will also provide a model to understand the cellular and molecular changes following epithelial damage resulting from other mechanical stresses (such as phonatrauma) and chemical stresses (such as acid reflux) which are implicated in the pathogenesis of common voice disorders.